Enhanced post-irradiation recovery of the hematopoietic system has been demonstrated in animals pretreated with a number of cytotoxic agents. While the basis for this radioprotective effect is unknown, the fact that cytotoxic agents with a wide variety of chemical properties are able to elicit the effect suggests that a common biological mechanism is involved which is independent of the metabolic pathway of the agent. In addition, as it is accepted that repair and renewal in the hematopoietic system is a function of its heterogeneous stem cell compartment, the mechanism most probably is linked to the dynamic aspects of stem cell heterogeneity. We propose a series of studies on the hematopoietic pluripotential stem cells (HPSC) that will define (1) the most efficacious scheduling of VcR and radiation (200R-600R) for reduction of radiation toxicity to the HPSC population, (2) the heterogeneity present in the HPSC population with respect to such parameters as self-renewal potential, radiosensitivity and cell cycle state and (3) the radioresponse of the tumor cells to pretreatment with VcR. Emphasis will be placed on the fractionation of the HPSC into subpopulations by physical and immunological techniques, and the characterization of these subpopulations by in vivo and in vitro clonogenicity, cell cycle state and self-renewal potential in an effort to monitor any changes in the recruitment of these subpopulations following various radiation-drug treatments. Ultimately, these studies will allow a better understanding of the organization of the hematopoietic stem cell compartment, the heterogeneity present and the kinetics of recruitment, self-renewal and proliferative capacity following perturbation which could potentially lead to a better therapeutic balance between tumor cell kill and normal cell recovery. In addition, elucidation of some basic principles of repair and renewal in normal tissues may be obtained.